1-acyl substituted quinolizines and process for their production



United States Patent 3,222,367 l-ACYL SUBSTITUTED QUINOLIZINES AND PROCESS FOR THEIR PRODUCTION Richard E. Brown, Hanover, and Robert I. Meltzer, Rockaway, N.J., assignors to Warner-Lambert Pharmaceutical Company, Morris Plains, N..I., a corporation of Delaware No Drawing. Filed July 16, 1963, Ser. No. 295,540 4 Claims. (Cl. 260-289) This invention relates to certain substituted quinolizines. More particularly, this invention relates to l-acyl substituted quinolizines of the formula:

wherein R and R each represents hydrogen, hydroxy, or lower alkoxy such as methoxy, ethoxy or propoxy; R represents hydrogen or lower alkyl such as methyl, ethyl or propyl, R represents lower alkyl such as methyl, ethyl, propyl and butyl, and n is an integer of 1 or 2, and to the non-toxic pharmaceutically acceptable acid addition salts thereof. This invention also includes within its scope a novel process for the production of these l-acyl substituted quinolizines.

The numbering of the compounds of this invention when n is 2 is as follows:

Exemplary of the novel l-acyl substituted quinolizines are:

1,2,3,3a,5,6,10b,11,12,12a-decahydro-1-acetyl-8,9- dimethoxy-l 2a-methyl-benz[a] cyclopenta [f] quinolizine,

1,2,3,3a,5,6,10b,11,12,12a-decahydro-1-acetyl-8- methoxy-l Za-methyl-benz [a] cyclopenta [f] quinolizine,

3,222,367 Patented Dec. 7, 1965 1,2,3 ,3a,5,6,l0b,11,12,12a-decahydro-l-propionyl-S- methoxy-l Za-methyl-benz [a] cyclopenta [f] quinolizine,

l,2,3,3 a,5,6,10b,l1,12,12a-decahydro-l-propionyl-S- hyd roxy- IZa-methyl-benz [a] cyclopenta [f quinolizine, and the like.

In the above equation, the symbols R R R R and n have the same meaning as defined.

The preparation of the material used in this reaction is described and claimed in our co-pending application, Serial No. 248,872, filed January 2, 1963.

Generally, the above-described reaction is carried out by treating a suspension of the starting material in an anhydrous inert solvent with the selected organo lithium compound. The resulting mixture is then stirred at ambient temperature, such as 20 to 30 C. for a period of about minutes, after which the mixture is hydrolysed with water. The desired reaction product can be readily recovered from the aqueous layer by extracting with solvents, such as ethyl acetate. As suitable solvents for the reaction, there may be mentioned for example, dry tetrahydrofuran, petroleum ether, diethyl ether and the like.

It is to be understood that the new and novel compounds of this invention may be used as the free base or may be converted into the corresponding nontoxic pharmaceutically acceptable acid addition salts. Exemplary of nontoxic acid addition salts are those formed with maleic, fumaric, benzoic, ascorbic, succinic, bismethylensalicyclic, methylsulfonic, ethanedisulfonic, acetic, propionic, tartaric, salicylic, citric, gluconic, lactic, malic, mandelic, cinnamic, citraconic, stearic, palmitic, icaconic, glycolic, benzenesulfonic, hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, and nitric acids. The acid addition salts may be prepared in the conventional manner, for example, by treating a solution or suspension of the free base in an organic solvent with the desired acid and then recovering the salt which forms by crystallization techniques.

In order to further illustrate this invention, the following examples are given. All temperatures are given in the centigrade scale.

EXAMPLE 1 Preparation of 1,2,3,3a,5,6,10b,1J,12,12a-decahydr0-1- acetyl-8,9-dimeth0xy IZa-methylbenz [a] cyclopentaU] quinolizine A suspension of 2.0 g. of l,2,3,3a,5,6,l0b,ll,l2,l2a,- decahydro 1 carboxy 8,9 dirnethoxy 12a methyl- 3 benz[a] cyclopenta[f]quinolizine hydrochloride in 100 ml. of dry tetrahydrofuran is treated with a solution of 25 millimoles of methyl lithium in 25 m1. of anhydrous ether dropwise over a period of 30 minutes. The mixture is then stirred at room temperature for 2 hours. There is then added 100 ml. of water, and the tetrahydrofuran is removed by distillation. The aqueous solution is extracted with ethyl acetate. The ethyl acetate solution is dried over sodium sulfate and the ethyl acetate is removed by distillation. The residue is taken up in ethanol and cooled slowly to give 1,2,3,3a,5,6,10b,11, 12,12a decahydro 1 acetyl 8,9 dimethoxy 12amethylbenz[a] cyclopenta[f]quinolizine as a white solid which after recrystallization from ethanol has a M.P. of l246.

EXAMPLE 2 Preparation of 1,2,3,3a,5,6,10b,]!,12,12a-decahydr-I- acetyl 8 methoxy 12a methylbenz[a]cyclopenta- [f] quinolizine In the same way as described in Example 1, 2.0 g. of l,2,3,3a,5,6,10b,11,12,12a decahydro 1 carboxy 8- methoxy 12a methylbenz[a]cyclopenta[f]quinolizine hydrochloride on reaction with methyl lithium gives 1,2,3,3a,5,6,l0b,l1,12,12a decahydro 1 acetyl 8- methoxy 12a methylbenz[a]cyclopenta[f]quinolizine as white crystals, M.P. 124-5 after recrystallization from aqueous-ethanol.

EXAMPLE 3 Preparation of 1,2,3,3a,5,6,10b,11,12,12a-decahydr0-1- valeryl 8 methoxy 12a methyl benz[a] cyclopenta [flquinolizine hydrobromide I In the same Way as described in Example 1, 2.0 g. of 1,2,3,3a,5,6,l0b,11,12,12a decahydro 1 carboxy 8- methoXy 12a methylbenz[a] cyclopenta[f]quinolizine hydrochloride in 100 ml. of dry tetrahydrofuran is treated with a solution of 25 millimoles of butyllithium in heptane to give 1,2,3,'3a,5,6,10b,11,'12,l2a-deoahydro-1-valeryl 8 methoxy 12a methylbenz[a]cyc1openta[f] quinolizine which gives a hydrobromide as white crystals, M.P. 206-8.

It is to be understood that the foregoing detailed description is given merely by way of illustration and that many variations may be made therein without departing from the spirit of our invention.

Having described our invention, what we desire to secure by Letters Patent is:

l. A member selected from the group consisting of compounds of the formula:

wherein R and R is each a member selected from the group consisting of hydrogen, hydroxy, and lower alkoxy; R is a member selected from the group consisting of hydrogen and lower alkyl; R; is lower alkyl and n is an integer from 1 to 2, and the nontoxic pharmaceutically acceptable acid addition salts thereof.

2. l,2,3,3a,5,6,10b,11,12,12a decahydro 1 acetyl- 8,9 dimethoxy 12a methyl benz[a]cyclopenta[f] quinolizine.

, 3. 1,2,3,3a,5,6,10b,l1,12,12a decahydro 1 acetyl 8- methoxy 12a methyl benz[a] cyclopenta[f] quinolizine.

4. 1,2,3,3a,5,6,10b,11,12,12a decahydro l valeryl- 8 methoxy 12a methyl benz[a] cyclopenta[f]quinolizine hydrobromide.

References Cited by the Examiner Fieser et al.: Advanced Organic Chemistry, Reinhold, 1961, pp. 400-401 relied on.

NICHOLAS S. RIZZO, Primary Examiner.

DONALD G. DAUS, Assistant Examiner. 

1. A MEMBER SELECTED FROM THE GROUP CONSISTING OF COMPOUNDS OF THE FORMULA: 